Neurology News

Several distinct groupings of neurons connected inside and across critical parts of the brain assist learning, remembering, and retrieving memories. A recent study led by the universities of Bristol and Heidelberg discovered that if these neuronal assemblies fail to sync up at the correct time, memories are lost.

How do you keep track of what to do next? What happens in the brain when your mind goes blank? Short-term memory relies on two key brain regions: the hippocampus and the prefrontal cortex. The researchers set out to establish how these brain regions interact with one another as memories are formed, maintained and recalled at the level of specific groups of neurons. The study, published in Currently Biology, also wanted to understand why memory sometimes fails. “Neural assemblies” — groups of neurons that join forces to process information — were first proposed over 70 years ago, but have proved difficult to pinpoint.

Using brain recordings in rats, the research team has shown that memory encoding, storage and recall are supported by dynamic interactions incorporating multiple neural assemblies formed within and between the hippocampus and prefrontal cortex. When the coordination of these assemblies fails, the animals made mistakes.

Dr Michal Kucewicz, Assistant Professor of Neurology at the Gdansk University of Technology, formerly a PhD student at the University of Bristol, and lead author, said: “Our results make potential therapeutic interventions for memory restoration more challenging to target in space and time. On the other hand, our findings have identified critical processes that determine success or failure in remembering. These present viable targets for therapeutic interventions on the level of neural assembly interactions.”

Matt Jones, Professor of Neuroscience in the School of Physiology, Pharmacology and Neuroscience and Bristol Neuroscience and senior author of the paper, added: “Our findings add to evidence that the neural substrates of memory are more distributed in anatomical space and dynamic across time than previously thought based on the neuropsychological models.”

The next steps for the research would be to modulate neural assembly interactions, either using drugs or via brain stimulation, which Dr Kucewicz is currently doing in human patients, to test whether disrupting or augmenting them would impair or enhance remembering. The research team presumes the same mechanisms would work in human patients to restore memory functions impaired in a particular brain disorder.

Dementia is a major global public health hazard that currently affects 50 million people and is expected to impact more than 150 million people by 2050. Obesity, as measured by the body mass index, is a persistent global issue (BMI). Obesity in middle age has been linked to an increased risk of dementia in previous studies. However, it is yet uncertain if BMI and dementia risk are linked.

Researchers from Boston University Chobanian & Avedisian School of Medicine and the Chinese Academy of Medical Sciences & Peking Union Medical College have shown that various patterns of BMI changes during a person’s life cycle may be a predictor of dementia risk.

“These findings are important because previous studies that looked at weight trajectories didn’t consider how patterns of weight gain/stability/loss might help signal that dementia is potentially imminent,” explained corresponding author Rhoda Au, PhD, professor of anatomy and neurobiology.

“These findings are important because previous studies that looked at weight trajectories didn’t consider how patterns of weight gain/stability/loss might help signal that dementia is potentially imminent,” explained corresponding author Rhoda Au, PhD, professor of anatomy and neurobiology.

A set of individuals in the Framingham Heart Study were tracked for 39 years and their weight was assessed every 2-4 years. The researchers studied distinct weight trends (stable, growth, loss) between people who became demented and those who did not. They discovered that the general trend of decreased BMI was linked to an increased chance of getting dementia.

Further investigation revealed a subgroup with a trend of first increasing BMI followed by dropping BMI, both happening within midlife, which looked to be key to the declining BMI-dementia connection.
Weight monitoring is generally simple for people, family members, and primary care providers, according to Au.

“If after a steady increase in weight that is common as one gets older, there is an unexpected shift to losing weight post midlife, it might be good to consult with one’s healthcare provider and pinpoint why. There are some potential treatments emerging where early detection might be critical in the effectiveness of any of these treatments as they are approved and become available,” she added.

The researchers hope this study will illustrate that the seeds for dementia risk are being sowed across many years, likely even across the entire lifespan. “Dementia is not necessarily inevitable and monitoring risk indicators such as something as easy to notice as weight patterns, might offer opportunities for early intervention that can change the trajectory of disease onset and progression.”

Strokes are a major source of morbidity and mortality in the United States and around the world. A number of environmental and biological factors have been identified as influencing stroke risk and outcome.

A new study sponsored by Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, examined the cerebral blood flow (CBF) modulation of stroke patients. The researchers discovered that cerebral autoregulation (CA), one of the fundamental processes for maintaining adequate blood flow to the brain, had a daily rhythm in stroke patients, with more deteriorated regulation during the night and morning hours compared to the afternoon hours.

Their results, which are published in the Journal of Cerebral Blood Flow and Metabolism, are relevant for health care planning during stroke recovery.

“The care and course of actions done after a stroke are essential for optimal rehabilitation. Our study suggests that the daily rhythm of CBF regulation in stroke patients may be highly relevant to managing an individual’s activity and stroke recovery,” said senior author, Kun Hu, PhD, of the Medical Biodynamics Program in the Brigham’s Division of Sleep and Circadian Disorders.

Kun added, “Exercise and surgery post-stroke could be more optimal when scheduled during afternoon hours, as this is when dynamic CA functions more effectively. These results may improve our understanding of a vulnerable time window for the cerebrovascular system and help guide daily activity and personal care during stroke recovery, which could improve health outcomes for patients who have had a stroke.”

Stable CBF is a necessary component for normal brain function. Dramatic changes in CBF can cause increased cranial pressure and brain tissue damage. Thus, a process like CA, which helps maintain relatively stable CBF through constriction and dilation of blood vessels in the brain, particularly during changes in an individual’s blood pressure (BP), is crucial.

Currently, there is a gap in knowledge concerning the daily variance of CA in stroke patients. Generally, the daily rhythms of physiological functions can be controlled by external behaviors like food intake, sleep, and exercise, as well as the internal circadian clock. This study is among the first to examine the potential variation of CA in the stroke population.

The research team observationally studied 28 participants being treated in a hospital in Sao Paulo, Brazil after experiencing a stroke. They received thrombolysis within 5 hours of the onset of their symptoms. After undergoing this procedure, the participants’ CA was assessed over the course of 48 hours at various time points by examining the relationship between temporal changes in blood pressure and cerebral blood flow velocity of the middle cerebral artery.

Analysis of the results showed evidence of differing cerebral blood flow regulation during various times of the day, especially when cerebral blood flow and pressure fluctuated at large time scales or low frequencies < 0.05 Hz. In particular, a more degraded regulation motif was seen during the nighttime and morning hours when compared to the afternoon. This dysregulation interval coincides with the increased prevalence of recurrent and first-ever stroke events during morning times.

While these results are promising, the researchers identified future avenues to assist in creating a greater understanding of the regulation mechanism.

“Interestingly, the daily rhythm of CA was present in both stroke and non-stroke sides of the brain, suggesting the factor(s) driving the rhythm should affect CBF regulation globally,” said first author Daniel Abadjiev, of the Medical Biodynamics Program in the Brigham’s Division of Sleep and Circadian Disorders. “To better understand underlying mechanisms, future studies should consider more frequent assessments across the 24-hour cycle, an increase in patient sample size, the inclusion of non-stroke controls, and monitoring of the daily activity rhythms like sleep and exercise as well as intrinsic circadian rhythm among the participants.”

“This study demonstrates that a daily rhythm does exist for stroke patients,” said Hu. “Rehab plans should look to identify the daily rhythm and design a strategy that makes use of optimal CA. The long-term goal is to see if we can further control the rhythm of CA by manipulating an individual’s daily behavioral cycles or endogenous circadian clock in order to deliver more personalized medicine and improve their recovery.”

The prospect of treating Alzheimer’s disease and other neurodegenerative diseases by infusing healthy, new immune cells into the brain has expanded dramatically. Researchers from the Universities of California, Irvine, and Pennsylvania have successfully overcome the brain’s resistance to them, so overcoming a significant barrier.

Their discovery of microglia, a type of brain cell, opens up a new universe of therapeutic and preventive alternatives for neurodegenerative illnesses.

In the Journal of Experimental Medicine, the team’s paper is published. When microglia are healthy, they serve as the central nervous system’s resident front-line disease warriors. “However, there is overwhelming evidence that they can become dysfunctional in many neurological conditions,” said Mathew Blurton-Jones, UCI professor of neurobiology & behaviour and study co-lead author, adding, “Until recently, scientists have mainly been looking at the mechanisms that drive microglial dysfunction and trying to find drugs to change their activity. But with this study, we’ve found a way to harness microglia themselves to treat those diseases potentially.”

Frederick ‘Chris’ Bennett, assistant professor of psychiatry at Penn and co-lead author, added: “There is an obstacle because once our own microglia develop in the location where they are supposed to be in our brains, they don’t give up that space. They block the ability to deliver new cells that would take their place. If you want to insert donor microglia, you have to deplete the host microglia to open up the room.”

Bennett and his laboratory partnered with Blurton-Jones and his lab on the project.

Microglia depend on signalling by a protein on their surface called CSF1R for their survival. The FDA-approved cancer drug pexidartinib has been found to block that signalling, killing them. This process would seem to offer a way to clear space in the brain to insert healthy donor microglia. However, there is a dilemma – unless the pexidartinib is stopped before the donor microglia are added, it will eliminate them, too. But once the drug is terminated, the host microglia regenerate too fast to effectively put in the donor cells.

This quandary has challenged efforts to treat people with certain rare and severe neurologic conditions. One is Krabbe disease, in which the body’s cells can’t digest certain fats that are highly abundant in the brain. Currently, clinicians use bone marrow transplantation and chemotherapy to try to introduce new immune cells similar to microglia into the brain. But this approach can be toxic and must be carried out before Krabbe symptoms manifest.

“Our team believed that if we could overcome the brain’s resistance to accepting new microglia, we could successfully transplant them into patients using a safer, more effective process in order to target a great number of diseases,” said co-first author Sonia Lombroso, a Penn PhD student and member of the Bennett Lab, adding, “We decided to investigate whether we could make the donor microglia resistant to the drug that eliminates their host counterparts.”

The researchers used CRISPR gene-editing technology to create one amino acid mutation, known as G795A, which they introduced into donor microglia produced from human stem cells or a mouse microglial cell line. Then they injected the donor microglia into humanized rodent models while administering pexidartinib, with exciting results.

“We discovered that this one small mutation caused the donor microglia to resist the drug and thrive, while the host microglia continued to die off,” said co-first author Jean-Paul Chadarevian, a UCI PhD student who is a member of the Blurton-Jones Lab, adding, “This finding could lead to many options for developing new microglial-based treatments. Pexidartinib is already approved for clinical use and appears to be relatively well tolerated by patients.”

Approaches could range from fighting disease by replacing dysfunctional microglia with healthy ones to designing microglia that can recognize imminent threats and strike against them with therapeutic proteins before they cause harm.
The UCI-Penn team believes treatments based on this kind of microglial method could be developed within a decade. Their subsequent investigations include studying in rodent models how to use the approach to attack the brain plaques associated with Alzheimer’s and to counter Krabbe and other similar diseases.

According to new research, adults who sustained any form of brain injury during a 30-year study period had double the rate of mortality as those who did not, and mortality rates among those with moderate or severe head injuries were nearly three times higher.

The study’s findings were reported in JAMA Neurology. Over 23 million persons aged 40 and over in the United States report a history of head injury with loss of consciousness. Head injuries can be caused by a variety of factors, including car accidents, inadvertent falls, and sports injuries. Furthermore, brain damage has been related to a variety of long-term health issues such as disability, late-onset epilepsy, dementia, and stroke.

Studies have previously shown increased short-term mortality associated with head injuries primarily among hospitalized patients. This longitudinal study evaluated 30 years of data from over 13,000 community-dwelling participants (those not hospitalized or living in nursing home facilities) to determine if a head injury has an impact on mortality rates in adults over the long term. Investigators found that 18.4 per cent of the participants reported one or more head injuries during the study period, and of those who suffered a head injury, 12.4 per cent were recorded as moderate or severe. The median period of time between a head injury and death was 4.7 years.

Death from all causes was recorded in 64.6 per cent of those individuals who suffered a head injury, and in 54.6 per cent of those without any head injury. Accounting for participant characteristics, investigators found that the mortality rate from all causes among participants with a head injury was 2.21 times the mortality rate among those with no head injury. Further, the mortality rate among those with more severe head injuries was 2.87 times the mortality rate among those with no head injury.

“Our data reveals that head injury is associated with increased mortality rates even long-term. This is particularly the case for individuals with multiple or severe head injuries,” explained the study’s lead author, Holly Elser, MD, PhD, MPH a Neurology resident at Penn. “This highlights the importance of safety measures, like wearing helmets and seatbelts, to prevent head injuries.”

Investigators also evaluated the data for specific causes of death among all participants. Overall, the most common causes of death were cancers, cardiovascular disease, and neurologic disorders (which include dementia, epilepsy, and stroke). Among individuals with head injuries, deaths caused by neurologic disorders and unintentional injury or trauma (like falls) occurred more frequently.

When investigators evaluated specific neurologic causes of death among participants with head injury, they found that nearly two-thirds of neurologic causes of death were attributed to neurodegenerative diseases, like Alzheimer’s and Parkinson’s disease. These diseases composed a greater proportion of overall deaths among individuals with head injury (14.2 per cent) versus those without (6.6 per cent).

“Study data doesn’t explain why the cause of death in individuals with head injuries is more likely to be from neurodegenerative diseases, which underscores the need for further research into the relationship between these disorders, head injury, and death,” said Andrea L.C. Schneider, MD, PhD, an assistant professor of Neurology at Penn.

According to new research, adults who had any type of brain damage during a 30-year study period had double the rate of mortality as those who did not, while mortality rates among those with moderate or severe head injuries were nearly three times higher.

The study’s findings were reported in JAMA Neurology. Over 23 million persons aged 40 and over in the United States report a history of head injury with loss of consciousness. Head injuries can be caused by a variety of factors, including car accidents, inadvertent falls, and sports injuries. Furthermore, brain damage has been related to a variety of long-term health issues such as disability, late-onset epilepsy, dementia, and stroke.

Previous research has found an increase in short-term mortality related with head injuries, particularly among hospitalised patients. This 30-year study examined data from over 13,000 community-dwelling individuals (those who were not hospitalised or living in nursing home facilities) to see if a brain injury affects adult mortality rates in the long term. The researchers discovered that 18.4% of the individuals reported one or more head injuries throughout the study period, and 12.4% of those who sustained a head injury were classified as moderate or severe. The median interval between sustaining a head injury and dying was 4.7 years.

Death from any cause was documented in 64.6 percent of those who experienced a head injury and in 54.6 percent of those who did not suffer a head injury. After controlling for participant characteristics, researchers discovered that the mortality rate from all causes among people with a head injury was 2.21 times that of those without a head injury. Furthermore, the mortality rate for those with more severe head injuries was 2.87 times that of those without a head injury.

“Our data reveals that head injury is associated with increased mortality rates even long-term. This is particularly the case for individuals with multiple or severe head injuries,” explained the study’s lead author, Holly Elser, MD, PhD, MPH a Neurology resident at Penn. “This highlights the importance of safety measures, like wearing helmets and seatbelts, to prevent head injuries.”

The data was also analysed for specific causes of death across all individuals by the investigators. Cancer, cardiovascular disease, and neurologic illnesses were the leading causes of mortality overall (which include dementia, epilepsy, and stroke). Deaths from neurologic illnesses and unintentional damage or trauma (such as falls) occurred more commonly among people with head injuries.

When researchers examined specific neurologic causes of mortality among participants with head injuries, they discovered that neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease accounted for approximately two-thirds of all neurologic causes of death. These diseases accounted for a higher proportion of overall mortality among people who had suffered a head injury (14.2%) than those who did not (6.6 per cent).

“Study data doesn’t explain why the cause of death in individuals with head injuries is more likely to be from neurodegenerative diseases, which underscores the need for further research into the relationship between these disorders, head injury, and death,” said Andrea L.C. Schneider, MD, PhD, an assistant professor of Neurology at Penn.

According to University of East Anglia research, hormone replacement therapy (HRT) might help prevent Alzheimer’s disease in women at risk of getting the condition. According to the findings, HRT usage is connected with improved memory, cognition, and bigger brain volumes in later life in women who possess the APOE4 gene, which is the greatest risk factor gene for Alzheimer’s disease.

HRT was most beneficial when administered early in the menopausal journey, during perimenopause, according to the research team. Prof Anne-Marie Minihane of the University of East Anglia’s Norwich Medical School and head of the Norwich Institute for Healthy Aging at UEA conducted the study with Prof Craig Ritchie of the University of Edinburgh.

Prof Minihane said, “We know that 25 per cent of women in the UK are carriers of the APOE4 gene and that almost two thirds of Alzheimer’s patients are women. In addition to living longer, the reason behind the higher female prevalence is thought to be related to the effects of menopause and the impact of the APOE4 genetic risk factor being greater in women.”
“We wanted to find out whether HRT could prevent cognitive decline in at-risk APOE4 carriers,” she added.

The study looked at data from 1,178 women who took part in the European Prevention of Alzheimer’s Dementia programme, which was designed to track participants’ brain health over time. The experiment covered ten nations and monitored individuals’ brains from ‘healthy’ to dementia in certain cases. Participants were eligible if they were over the age of 50 and did not have dementia. The researchers examined their findings to determine the effect of HRT on women with the APOE4 genotype.

Dr Rasha Saleh, also from UEA’s Norwich Medical School, said, “We found that HRT use is associated with better memory and larger brain volumes among at-risk APOE4 gene carriers. The associations were particularly evident when HRT was introduced early — during the transition to menopause, known as perimenopause.”

“This is really important because there have been very limited drug options for Alzheimer’s disease for 20 years and there is an urgent need for new treatments. The effects of HRT in this observation study, if confirmed in an intervention trial, would equate to a brain age that is several years younger,” she added.

Prof Anne Marie Minihane said, “Our research looked at associations with cognition and brain volumes using MRI scans. We did not look at dementia cases, but cognitive performance and lower brain volumes are predictive of future dementia risk.”
Prof Michael Hornberger, from UEA’s Norwich Medical School, said, “It’s too early to say for sure that HRT reduces dementia risk in women, but our results highlight the potential importance of HRT and personalised medicine in reducing Alzheimer’s risk.”

“The next stage of this research will be to carry out an intervention trial to confirm the impact of starting HRT early on cognition and brain health. It will also be important to analyse which types of HRT are most beneficial,” he added.
Prof Craig Ritchie, from the University of Edinburgh, said, “This important finding from the EPAD Cohort highlights the need to challenge many assumptions about early Alzheimer’s disease and its treatment, especially when considering women’s brain health. An effect on both cognition and brain changes on MRI supports the notion that HRT has tangible benefit. These initial findings need replication however in other populations.”